Abstract
Hereditary spastic paraplegia (HSP) is an inherited neurological condition that leads to progressive spasticity and gait abnormalities. Adult-onset HSP is most commonly caused by mutations in SPAST, which encodes spastin a microtubule severing protein. In olfactory stem cell lines derived from patients carrying different SPAST mutations, we investigated microtubule-dependent peroxisome movement with time-lapse imaging and automated image analysis. The average speed of peroxisomes in patient-cells was slower, with fewer fast moving peroxisomes than in cells from healthy controls. This was not because of impairment of peroxisome-microtubule interactions because the time-dependent saltatory dynamics of movement of individual peroxisomes was unaffected in patient-cells. Our observations indicate that average peroxisome speeds are less in patient-cells because of the lower probability of individual peroxisome interactions with the reduced numbers of stable microtubules: peroxisome speeds in patient cells are restored by epothilone D, a tubulin-binding drug that increases the number of stable microtubules to control levels. Patient-cells were under increased oxidative stress and were more sensitive than control-cells to hydrogen peroxide, which is primarily metabolised by peroxisomal catalase. Epothilone D also ameliorated patient-cell sensitivity to hydrogen-peroxide. Our findings suggest a mechanism for neurodegeneration whereby SPAST mutations indirectly lead to impaired peroxisome transport and oxidative stress.
Highlights
Hereditary spastic paraplegia (HSP) is an inherited neurological condition that leads to progressive spasticity and gait abnormalities
We show here that microtubule-dependent peroxisome transport is severely impaired, along several dimensions, in axon-like processes in HSP patient cells with SPAST mutations
In the undifferentiated ONS cells, the mean peroxisome speed in patient cells was lower by about 10% compared to control cells[13]
Summary
Hereditary spastic paraplegia (HSP) is an inherited neurological condition that leads to progressive spasticity and gait abnormalities. The average speed of peroxisomes in patientcells was slower, with fewer fast moving peroxisomes than in cells from healthy controls This was not because of impairment of peroxisome-microtubule interactions because the time-dependent saltatory dynamics of movement of individual peroxisomes was unaffected in patient-cells. In patient cells with heterozygous SPAST mutations there were reduced levels of acetylated α-tubulin, a marker for stabilised microtubules, and reduced speeds of peroxisome transport both of which were restored to control levels by low doses of several tubulin-binding drugs[15]. Patient cells have less acetylated α-tubulin than control cells, indicating fewer stabilised microtubules This could reduce the probability of peroxisome-microtubule interactions and restrict the number of peroxisomes being able to move along microtubules thereby reducing the average speed of the peroxisome population. This mechanism was assessed by comparing the numbers of peroxisomes moving at different speeds, with an emphasis on the fastest group of peroxisomes, those whose movement is unequivocally microtubule-dependent
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